B lymphocytes produce five classes of immunoglobulins, which mediate different functions. IgM is most effective in complement fixation, IgG causes opsonization and cellular cytotoxicity and can cross the placenta. IgA functions on the mucosal surface and IgE mediates degranulation of mast cells and basophils. The function of IgD is still not well understood. These antibodies are present in the blood circulation, with IgG, IgA, and IgM being the major serum components.
In addition to secreting immunoglobulins, the B cells also express different isotypes of the immunoglobulins on their cell surfaces at different stages of maturation. IgM and IgD are present on the surface of resting, uncommitted B cells, while often only one of the five classes of immunoglobulins may exist on late stage, mature B cells, which secrete the same immunoglobulin isotype as expressed on their cell surface. Teale, J.M., et al., J. Immunol. 1126:1952-1957 (1981); Gathings, W. E., et al., Immunol. Rev. 57:107-126 (1981); Teale, J. M., Fed. Proc. 41:5-9 (1982).
Numerous pathogenic microorganisms, such as bacteria and viruses, enter the body through the respiratory, gastrointestinal, and genitourinary tracts during air inhalation, food and liquid intake, and sexual contact. The potentially allergenic substances, e.g., tree, grass, and flower pollens, dust mites, fungal particles and animal dander, also enter the body through the respiratory tract. Secretory IgA antibodies help to defend against these pathogens and allergens.
IgA is produced by plasma cells located along the mucosal linings of the aforementioned tracts, which are all exposed to the external environment. The .alpha. chain and light chain immunoglobulins produced by plasma cells combine with a secretory component produced by the epithelial cells in the mucosal tissues, forming secretory IgA molecules that are secreted to the surface of mucosal layers. See generally J. G. Nedrud et al., "Adjuvants and the Mucosal Immune System", Topics in Vaccine Adjuvant Research, (Spiggs, D. E., Koff, W. C., Eds.) CRC Press, Boca Raton, Fla. (1990). These secretory IgA molecules bind to the invading pathogens and weaken their ability to penetrate the mucosal layer and to enter the inner tissue and blood stream of the host. See generally J. G. Nedrud et al., "Adjuvants and the Mucosal Immune System", Topics in Vaccine Adjuvant Research, (Spiggs, D. E., Koff, W. C., Eds.) CRC Press, Boca Raton, Fla. (1990). IgA can also bind allergenic substances, thereby preventing the allergens from binding IgE or activating the T cells responsible for delayed-type hypersensitivity.
It has been found that individuals with low IgA production are more prone to various infectious diseases and have a higher tendency to develop allergic diseases than those with normal IgA levels. Thus if the levels of either total IgA or antigen-specific IgA can be increased, the diseases or allergies may be prevented.
It is also well known that various allergenic substances enter through inhalation and food ingestion, causing immediate-type, antibody-mediated hypersensitivities and delayed-type, cell-meditated hypersensitivities. In sensitized individuals, the IgE-mediated reactions against pollens, animal danders, dust mites, and other allergenic antigens cause the common allergic symptoms, such as allergic rhinitis ("hay fever") and extrinsic asthma. In such allergic responses, the allergens enter the mucosal layers of the respiratory tracts and nasal linings and bind to allergen-specific IgE which is on the surface of basophils and mast cells. The binding of IgE by the allergens on the basophils and mast cell surface causes cross-linking of the underlying IgE Fc receptors, and triggers the release of histamines and other pharmacologic mediators, resulting in various allergic symptoms. In the cell-mediated hypersensitivities, certain T helper cells responsible for delayed-type hypersensitivity are activated. These T cells recruit and activate macrophages, causing inflammatory symptoms.
It has been shown that antibodies which bind to epitopes of B cell membrane-bound immunoglobulins can be used to eliminate B cells producing the immunoglobulins. In particular, antibodies specific for the antigenic epitope located on the transmembrane anchoring peptide of B cell membrane-bound (but not secreted) IgE can be used for removing IgE secreted B cells in patients suffering from IgE-mediated allergies, as described the published international PCT/US88/04706 patent application, filed Dec. 29, 1988.
Antibodies that belong to certain immunoglobulin classes and subclasses, such as murine IgG.sub.2a and human IgG.sub.1, and that bind with an appropriately high affinity to surface antigens of target cells can lyse those target cells. However, as noted above, not all antibodies specific for target cells will cause cytolysis, and some in fact cause isotype switching, proliferation, and increased or decreased antibody production. See Vitetta, E. D., et al., Immunol. Rev. 52:211-231 (198); Cooper, M. D., et al., Immunol. Rev. 52:29-53 (1980). In numerous studies, polyclonal antibodies have also been shown to induce B cell proliferation. See Sell, S. and Gell, P.G.H., J. Exp. Med. 122:423-44 (1965); Kishimoto, T., et al., J. Immunol. 115:1179-1184 (1975); Parker, D. C., Nature 258:361-363 (1975); Sieckmann, D. G., et al., J. Exp. Med. 147:814-829; Pure, E. and Vitetta, E. S., J. Immunol. 125:1240-1242 (1980). Unlike antibody-dependent cellular cytotoxicity and complement-mediated cytolysis, this proliferative response does not seem to involve the Fc of the antibodies. It has been shown that F(ab').sub.2 is more effective than whole antibody in inducing the proliferative effect, Vitetta, E. S. et al., Immunol. Rev. 52:211-231 (1980), indicating the absence of Fc involvement.
Numerous investigators have studied effects of anti-Ig antibodies on the activity of B cells. A review article, "Effects of anti-immunoglobulin sera on B lymphocyte function", Immunol. Rev. Vol. 52, ed. by Moller, G. (1980), states that anti-Ig antibodies have a variety of effects on B cells, including the ability to cause proliferation of B cells. In addition, anti-IgM and anti-IgD antibodies appear to be able to switch the resting uncommitted B cells to producers of IgG and IgA. These studies show that divalent antibodies which cross-link the surface Ig are required to stimulate B cell proliferation. These effects do not require Fc portions of the antibodies and, in fact, the F(ab').sub.2 fragments appear to be more effective than whole IgG in stimulating B cell proliferation.
Proliferating B cell with anti-Ig antibodies seem highly desirable for enhancing antibody production in vivo. However, proliferation is difficult to achieve. Because of the large concentrations of IgG, IgM, and IgA antibodies in the circulation, anti-Ig antibodies which are administered will bind to the circulating Ig before they can bind to significant amounts of the surface Ig on B cells. What is needed is a B cell proliferative agent which reacts with membrane-bound immunoglobulins and causes proliferation or B cell modulation without reacting with the secreted, circulating immunoglobulins.